E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally-advanced or Metastatic Colorectal Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Cancer; Colon Cancer; Colorectal Cancer; Fever; Locally Advanced; Colorectal Cancer Metastatic; Neutropenia; Rectal Cancer |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of pegfilgrastim, as compared with placebo in
reducing the incidence of grade 3/4 febrile neutropenia (FN) in subjects with newly diagnosed, locally-advanced or metastatic colorectal cancer treated with bevacizumab and either FOLFOX or FOLFIRI.
Grade 3/4 FN is defined as:
• A temperature ≥ 38.0°C (≥ 100.4°F) and absolute neutrophil count
(ANC) < 1.0 × 109/L, where ANC is measured the same day or within
+/- 1 calendar day of a temperature ≥ 38.0°C (≥ 100.4°F).
• An ANC<1.0 × 109/L in combination with:
o Documented sepsis or infection, OR
o Neutropenia-related hospitalization
where ANC is measured the same day or within +/- 1 calendar day. |
|
E.2.2 | Secondary objectives of the trial |
To estimate the effects, if any, of pegfilgrastim on the efficacy of bevacizumab and chemotherapy compared with placebo as evaluated by overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).
To characterize the incidence of grade 4 FN, grade 3/4 neutropenia and grade 4 neutropenia. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease-related
• Histologically or cytologically-confirmed adenocarcinoma of the colon or rectum
• Locally-advanced or metastatic disease by radiographic evaluation (CT, MRI)
o Measurable disease as defined by revised RECIST Criteria (v1.1) criteria (see Appendix F)
• Subject has not previously received chemotherapy for locally-advanced or metastatic CRC
o Subject may have received adjuvant therapy for primary colorectal cancer provided that at least 6 months have elapsed from the time the adjuvant therapy was concluded and recurrent/metastatic disease was documented.
It is recommended that if progression occurred after 6 months but within 12 months following completion of adjuvant FOLFOX chemotherapy, subjects should receive FOLFIRI + bevacizumab as first-line chemotherapy, and vice versa. If > 12 months has elapsed before progression occurs, subjects may receive FOLFOX + bevacizumab or FOLFIRI + bevacizumab at physician’s discretion, regardless of what was received adjuvantly.
• ECOG performance status 0-2 (see Appendix E)
4.1.2 Demographic
• Age of 18 years or over
4.1.3 Laboratory
Adequate organ and marrow function as defined below:
• Absolute neutrophil count (ANC) at least 1.5 x 109/L
• Platelet count at least 100 x 109/L
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN or AST and ALT ≤ 5.0 x ULN if attributable to liver metastasis
• An in-range INR (in-range is usually defined as between 2 and 3) for
subjects on a stable dose of oral anticoagulant or stable dose of low
molecular weight heparin
• Subject has no active bleeding or pathological condition that carries high risk of bleeding (eg, tumor involving major vessels or known varices). If a suspicion of bleeding diathesis exists, a bleeding time should be performed.
• Creatinine ≤ 1.5 times ULN
4.1.4 General
• Written informed consent obtained
• Afebrile on day 1 of cycle 1
• Must be able and willing to comply with study and/or follow-up procedures |
|
E.4 | Principal exclusion criteria |
Disease-related
• Known brain metastases
• History of another primary malignancy less than/equal to 5 years prior to randomization, with the exception of non-melanoma skin cancer, carcinoma in situ of uterine cervix, and prostatic intraepithelial neoplasia without evidence of prostate cancer
• Prior major surgical procedure less than 28 days prior to day 1 of cycle 1 chemotherapy dosing); anticipated need for major surgical procedure during the 4 cycle treatment period of the study
• Fine needle aspirations or core biopsies within 7 days prior to day 1 of cycle 1 chemotherapy dosing
• Serious nonhealing wound, ulcer, or bone fracture, or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 1 of cycle 1
• Uncontrolled high blood pressure, history of labile hypertension, uncontrolled congestive heart failure, unstable angina within the past 3 months, myocardial infarction or history of stroke within the past 12 months, unstable symptomatic arrhythmia requiring medication, or clinically significant peripheral vascular disease
• History of clinically significant bleeding within 6 months prior to randomization
• History of arterial or venous thromboembolism within 6 months prior to randomization
• History of other disease including uncontrolled diabetes, serious active or uncontrolled infection, metabolic dysfunction; physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of the prescribed therapy or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications
4.2.2 Laboratory
• Proteinuria > 1+, or total quantitative protein > 500 mg protein/day as determined by 24-hr urine collection
4.2.3 Medications
• Prior radiotherapy unless treatment was limited to the target lesion and only 1 measurable lesion was treated. Progression of the irradiated lesion must be demonstrated. Subjects may not have received prior radiotherapy to greater than 25% of bone marrow. Radiation must have concluded ≥ 4 weeks prior to enrollment. Prior radio-sensitizing chemoradiation will be allowed as long as it was concluded ≥ 4 weeks prior to enrollment.
o Radiotherapy to non-target lesions for pain control will be allowed
• Prior bevacizumab use or other agents targeting VEGF
• Concurrent use of other biological agents
• Use of systemic anti-infectives for active infection, during the 3 calendar days before starting study chemotherapy and bevacizumab or planned during the study treatment period
General
• Current, recent (within 4 weeks of the first infusion of this study), or planned participation (during the study treatment period) in an experimental therapeutics study other than this protocol
• Female subjects who are pregnant or lactating or men and women of
reproductive potential not willing to employ an effective method of birth control during treatment and for 20 weeks for women, and 30 weeks for men after discontinuing study treatment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab, irinotecan, 5-FU, oxaliplatin, or leucovorin, including known sensitivity to E.Coli derived products (eg, Filgrastim, HUMULIN insulin, L-asparaginase)
• Known dihydropyrimidine dehydrogenase deficiency |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the incidence of grade 3/4 FN during the study treatment period.
The study will evaluate whether adding pegfilgrastim can reduce the incidence of grade 3/4 FN in first-line CRC patients receiving the combination of chemotherapy and bevacizumab. The study is designed to have at least 90% power at the two-sided 0.05 significance level to detect an absolute reduction of subject incidence of grade 3/4 FN
from 9% to 3%, which is approximately 66.7% relative reduction.
The definition of Grade 3/4 FN used for the primary analysis is defined below:
• A temperature ≥ 38.0ºC (≥ 100.4ºF) and absolute neutrophil count
(ANC) < 1.0 × 109/L, where ANC is measured the same day or within
+/- 1 calendar day of a temperature ≥ 38.0ºC (≥ 100.4ºF).
• An ANC<1.0 × 109/L in combination with:
o Documented sepsis or infection, OR
o Neutropenia-related hospitalization
where ANC is measured the same day or within +/- 1 calendar day. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
After the last subject has completed the treatment period of the study. |
|
E.5.2 | Secondary end point(s) |
The key secondary endpoints are OS and PFS. These are the efficacy endpoints of bevacizumab plus chemotherapy. PFS will be based on investigator radiologic assessment.
Additional secondary endpoints related to the efficacy of chemotherapy and bevacizumab are:
• TTP (based on investigator radiographic assessment)
• ORR (based on investigator radiographic assessment)
These endpoints will be evaluated at the end of the treatment period and at the end of study.
Additional neutropenia-related secondary endpoints (evaluated at end of study treatment period):
• Incidence of Grade 4 FN during treatment period
• Incidence of Grade 3/4 neutropenia during treatment period
• Incidence of Grade 4 neutropenia during treatment period |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
An interim analysis of OS and PFS and other tumor response endpoints (TTP and ORR) will be performed after the last subject has completed the treatment period of the study. The final analysis of OS and PFS and other tumor response endpoints (TTP and ORR) will occur after all subjects have completed long-term follow-up.
The additional neutropenia-related secondary endpoints will be evaluated at the end of the treatment period of the study. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Mexico |
Russian Federation |
Ukraine |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as when the last-enrolled participating subject completes the 36-month long-term follow-up period, or discontinues the study due to death, loss to follow-up, or study consent withdrawal. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |